Caveolin is a membrane scaffolding protein that is traditionally considered a marker of plasma membrane caveolae, membrane microdomains rich in cholesterol and glycosphingolipids. Originally regarded as fixation artifacts of electron microscopy, the functional role for caveolae has taken decades to unravel. The discovery of the caveolin protein in 1992 (by the late Richard G.W. Anderson) accelerated progress in defining the contribution of caveolae to cellular physiology and pathophysiology. The three isoforms of caveolin (caveolin-1, -2 and -3) appear to be ubiquitously expressed and regulate a variety of functions in many organs. A PubMed search for “caveolae” reveals ~280 publications from their discovery in the 1950s to the early 1990s whereas a search for “caveolae or caveolin” after 1990, identifies ~7400 entries. Most work on the regulation of biological responses by caveolae and caveolin since 1990 has focused on caveolae as plasma membrane microdomains and the function of caveolin proteins at the plasma membrane. Recent evidence from our group as well as others has localized caveolin to many other cellular organelles (e.g., endoplasmic reticulum, Golgi, mitochondria, and nucleus) and shown that the protein is active at these sites. Organelle specific caveolin localization appears to be critical for regulation of cellular physiology. The mitochondria are one such organelle that are critical to the regulation of cell death and survival. We show that caveolin localizes to outer and inner mitochondrial membrane, regulates mitochondrial structure, and is a major regulator of mitochondrial function under various stress conditions. We further show that mice overexpressing caveolin are adapted to a variety of acute and chronic physiological stressors and have limited age-associated decline of function. Both mice and C. elegans engineered to overexpress caveolin show increased lifespan and healthy aging. This preservation of function with age is dependent on regulated cycling of caveolin from membrane to mitochondria to maintain homeostasis. Importantly, the critical link between membrane caveolae, caveolin, and mitochondria appears to be a generalized, evolutionarily conserved mechanism of stress adaptation. Caveolin may be a major regulatory point for cell growth, survival, and death.